Hypercholesterolemia is an established risk factor in the development of atherosclerosis. Therapeutic agents which control the level of serum cholesterol have proven to be effective in the treatment of coronary artery disease. While agents exist that can modulate circulating levels of cholesterol-carrying lipoproteins, these agents have little or no effect on the intestinal absorption of cholesterol. Dietary cholesterol can increase the level of serum cholesterol to levels which place an individual at increased risk for the development or exacerbation of atherosclerosis. Since much of the free or unesterified cholesterol that is absorbed by intestinal mucosal cells must first be esterified by ACAT prior to its incorporation and secretion into the bloodstream in large lipoprotein particles called chylomicrons, inhibition of ACAT can reduce the absorption of dietary cholesterol. In addition, the accumulation and storage of cholesteryl esters in the arterial wall is associated with increased activity of ACAT. Inhibition of the enzyme is expected to inhibit the formation or progression of atherosclerotic lesions in mammals.
There are an increasing number of patents in the literature disclosing compounds which are useful as ACAT inhibitors in particular and antiatherosclerotic agents in general. For example, U.S. Pat. No. 4,623,662, issued to DeVries on Nov. 18, 1986, discloses ureas and thioureas as ACAT inhibitors useful for reducing the cholesterol ester content of an arterial wall, inhibiting atherosclerotic lesion development, and/or treatment of mammalian hyperlipidemia. U.S. Pat. No. 4,722,927, issued to Holmes on Feb. 2, 1988, discloses disubstituted pyrimidineamides of oleic and linoleic acids as ACAT inhibitors useful for inhibiting intestinal absorption of cholesterol. U.S. Pat. No. 4,824,843, issued to Hoefle et al. on Apr. 25, 1989, and the related U.S. Pat. No. 4,882,357, issued to Creger et al. on Nov. 21, 1989, disclose a series of substituted N-phenyl-2,2-dimethyl-5-aryloxypentanamides, which prevent the intestinal absorption of cholesterol in mammals by inhibiting ACAT. European Patent Application 325,397, filed by Ito on Jul. 26, 1989, discloses a series of compounds consisting of two N-cycloalkyl-N'-arylurea units linked at nitrogen by a dialkylphenyl unit, which are inhibitors of the ACAT enzyme. U.S. Pat. No. 4,868,210, issued to Trivedi on Sep. 19, 1989, and the related European Patent Applications 335,374 filed by Trivedi on Mar. 30, 1988, and 386,487, filed by Trivedi on Feb. 9, 1989, disclose certain N-2,6-dialkyl- or N-2,6-dialkoxyphenyl-N'arylalkyl ureas as potent inhibitors of ACAT. European Patent Application 354,994, filed by Meguro and Ikeda on Feb. 21, 1990, discloses certain N-aryl-N'-quinolin-4-yl ureas as ACAT inhibitors. European Patent Application 370,740, filed by Jackson et al. on Nov. 21, 1988, discloses ACAT inhibitors similar in composition to those of DeVries (supra).
The following references also disclose compounds which are inhibitors of ACAT useful as antihypercholesterolemic and/or antiatherosclerotic agents: U.S. Pat. No. 4,900,744; European Patent Application EP-A-372,445; International Application WO 91/09021; International Application WO 91/10662; International Application WO 91/13876; German Laid Open Application No. DE 3504679; German Laid Open Application No. DE 3504680; European Patent Application EP 418,071 A2, filed by McCarthy et al.; and International Application WO 92/09561, filed by Itih, et al. The compounds in these references are disclosed to be inhibitors of ACAT useful for the treatment of conditions such as atherosclerosis, hyperlipidemia, cholesterol ester shortage disease and atheroma in vein grafts.
Other patents of related structure are DE 3534765 A1, issued to Pieper et al. on Apr. 2, 1987, DE 3701517 A1 issued to Nickl et al on Aug. 4, 1988, U.S. Pat. No. 3,665,031, issued to Peterli et al. on May 23, 1972, U.S. Pat. No. 4,859,707, issued to Loftsson et al. on Aug. 22, 1989, International Patent Application WO 92/07825, filed by Sato et al., and International Patent Application WO 92/09572, filed by Sato et al.
There are no known literature references disclosing the substituted mandeloamides (.alpha.-alkoxyphenylacetamides), substituted thiomandeloamides sulfides (.alpha.-thioalkoxyphenylacetamides), .alpha.-alkoxyacetamides, .alpha.-thioalkoxyacetamides, .alpha.,.alpha.-difluoroacetamides, and .alpha.-ketoacetamides of this invention, their use as ACAT inhibitors, or their use to lower cholesterol or in the treatment of atherosclerosis. The invention of these compounds represents a potentially significant development in the area of treatment of atherosclerosis. The novel .alpha.-alkoxy-, .alpha.-thioalkoxy-, .alpha.,.alpha.-difluoro- and .alpha.-keto-acetamide compounds of the improved invention have improved potency and/or bioavailability.